Assessment of the uniform field electroretinogram for mouse retinal ganglion cell functional analysis.

PURPOSE: The uniform field electroretinogram (UF-ERG) has been suggested as an alternative to the pattern electroretinogram (PERG) for non-invasive assessment of retinal ganglion cell (RGC) function in primates. We evaluated the validity of the UF-ERG to assess mouse RGC activity in vivo. METHODS: Unilateral optic nerve crush (ONC) was performed on adult C57BL/6J mice. Contralateral eyes with uncrushed optic nerves and eyes from surgically naive mice served as experimental controls. Electrophysiological visual assessment was performed at 12 weeks post-ONC. Flash-mediated visual-evoked cortical potentials (VEPs) were measured to confirm the robustness of the ONC procedure. Full-field flash ERGs were used to interrogate photoreceptor and retinal bipolar cell function. RGC function was assessed with pattern ERGs. Summed onset and offset UF-ERG responses to alternating dark and light uniform field flash stimuli of different intensities and wavelengths were recorded from ONC and control eyes, and relative differences were compared to the PERG results. Following electrophysiological analysis, RGC loss was monitored by immunohistochemical staining of the RGC marker protein, RBPMS, in post-mortem retinal tissues. RESULTS: ONC dramatically impacts RGC integrity and optic nerve function, demonstrated by reduced RGC counts and near complete elimination of VEPs. ONC did not affect scotopic ERG a-wave and b-wave amplitudes, while PERG amplitudes of eyes subjected to ONC were reduced by approximately 50% compared to controls. Summation of ON and OFF UF-ERG responses did not reveal statistically significant differences between ONC and control eyes, regardless of visual stimulus. CONCLUSIONS: PERG responses are markedly impaired upon ONC, while UF-ERG responses are not significantly affected by surgical trauma to RGC axons in mice. The more closely related pattern and uniform field ERGs recorded in primates suggests species-specific differences in RGC features or subpopulations corresponding to PERG and UF-ERG response generators, limiting the utility of the UF-ERG for mouse RGC functional analysis.

Pathophysiology of central serous chorioretinopathy: a literature review with quality assessment.

The pathogenesis of central serous chorioretinopathy (CSCR), a pachychoroid disease, is poorly understood. While choroid hyperpermeability and retinal pigment epithelium dysfunction are cornerstones for developing CSCR, the mechanisms at the retinal, vascular, retinal pigment epithelium, and cellular level continue to be an enigma. A few preclinical studies and the development of small-sized, poorly controlled clinical trials have resulted in limited insight into the disease mechanism. Effective treatments for CSCR are still lacking as current trials have produced inconsistent results for functional and structural gains. Thus, critically evaluating the literature to explore disease mechanisms and provide an up-to-date understanding of pathophysiology can provide valuable information and avenues to new treatments. In this study, a comprehensive summary of the mechanistic insight into CSCR is presented while highlighting the shortcomings of current literature. The mechanism was divided into seven sub-categories including mechanical obstruction, inflammation, oxidative stress, paracrine factors, autonomic dysfunction, mineralocorticoid receptors activation, and medications. We implemented validated tools like the JBI and CAMARADES to objectively analyze the quality of both clinical and preclinical studies, respectively. Overall, our analysis of the literature showed that no single mechanism was populated with a large number of sufficiently sized and good-quality studies. However, compiling these studies gave hints not only to CSCR pathogenesis but also pachychoroid disease in general while providing suggestions for future exploration.

XIAP gene therapy effects on retinal ganglion cell structure and function in a mouse model of glaucoma.

Glaucoma is a prevalent neurodegenerative disease that is characterized by progressive visual field loss. It is the leading cause of irreversible blindness in the world. The main risk factor for glaucoma is elevated intraocular pressure that results in the damage and death of retinal ganglion cells (RGCs) and their axons. The death of RGCs has been shown to be apoptotic. We tested the hypothesis that blocking the activation of apoptosis may be an effective strategy to prevent RGC death and preserve functional vision in glaucoma. In the magnetic microbead mouse model of induced ocular hypertension, inhibition of RGC apoptosis was targeted through viral-mediated ocular delivery of the X-linked inhibitor of apoptosis (XIAP) gene, a potent caspase inhibitor. Pattern electroretinograms revealed that XIAP therapy resulted in significant protection of both somal and axonal RGC function in glaucomatous eyes. Histology confirmed that the treated optic nerves showed preservation of axon counts and reduced glial cell infiltration. These results show that XIAP is able to provide both functional and structural protection of RGCs in the microbead model of glaucoma and provide important proof-of-principle for XIAP's efficacy as a neuroprotective treatment for glaucoma.

Sensory Experience Modulates Atrx-mediated Neuronal Integrity in the Mouse Retina.

Mutation of the α-thalassemia/mental retardation syndrome X-linked protein, ATRX, causes intellectual disability and is associated with pleiotropic defects including ophthalmological abnormalities. We have previously demonstrated that Atrx deficiency in the mouse retina leads to the selective loss of inhibitory interneurons and inner retinal dysfunction. Onset of the amacrine cell neurodegenerative phenotype in Atrx-deficient retinas occurs postnatally after neuronal specification, and coincides with eye opening. Given this timing, we sought to interrogate the influence of light-dependent visual signaling on Atrx-mediated neuronal survival and function in the mouse retina. Retina-specific Atrx conditional knockout (cKO) mice were subjected to light deprivation using two different paradigms: (1) a dark-rearing regime, and (2) genetic deficiency of metabotropic glutamate receptor 6 (mGluR6) to block the ON retinal signaling pathway. Scotopic electroretinography was performed for adult dark-reared Atrx cKO mice and controls to measure retinal neuron function in vivo. Retinal immunohistochemistry and enumeration of amacrine cells were performed for both light deprivation paradigms. We observed milder normalized a-wave, b-wave and oscillatory potential (OP) deficits in electroretinograms of dark-reared Atrx cKO mice compared to light-exposed counterparts. In addition, amacrine cell loss was partially limited by genetic restriction of retinal signaling through the ON pathway. Our results suggest that the temporal features of the Atrx cKO phenotype are likely due to a combined effect of light exposure upon eye opening and coincident developmental processes impacting the retinal circuitry. In addition, this study reveals a novel activity-dependent role for Atrx in mediating post-replicative neuronal integrity in the CNS.

XIAP Protects Retinal Ganglion Cells in the Mutant ND4 Mouse Model of Leber Hereditary Optic Neuropathy.

Purpose: Leber hereditary optic neuropathy (LHON) is a genetic form of vision loss that occurs primarily owing to mutations in the nicotinamide adenine dinucleotide dehydrogenase (ND) subunits that make up complex I of the electron transport chain. LHON mutations result in the apoptotic death of retinal ganglion cells. We tested the hypothesis that gene therapy with the X-linked inhibitor of apoptosis (XIAP) would prevent retinal ganglion cell apoptosis and reduce disease progression in a vector-induced mouse model of LHON that carries the ND4 mutation. Methods: Adeno-associated virus (AAV) encoding full length hemagglutinin-tagged XIAP (AAV2.HA-XIAP) or green fluorescent protein (AAV2.GFP) was injected into the vitreous of DBA/1J mice. Two weeks later, the LHON phenotype was induced by AAV delivery of mutant ND4 (AAV2.mND4FLAG) to the vitreous. Retinal function was assessed by pattern electroretinography. Optic nerves were harvested at 4 months, and the effects of XIAP therapy on nerve fiber layer and optic nerve integrity were evaluated using immunohistochemistry, transmission electron microscopy and magnetic resonance imaging. Results: During LHON disease progression, retinal ganglion cell axons are lost. Apoptotic cell bodies are seen in the nuclei of astrocytes or oligodendrocytes in the optic nerve, and there is thinning of the optic nerve and the nerve fiber layer of the retina. At 4 months after disease onset, XIAP gene therapy protects the nerve fiber layer and optic nerve architecture by preserving axon health. XIAP also decreases nuclear fragmentation in resident astrocytes or oligodendrocytes and decreases glial cell infiltration. Conclusions: XIAP therapy improves optic nerve health and delays disease progression in LHON.

Comparison of the uniform-field electroretinogram and the pattern electroretinogram to checkerboard and bar gratings.

PURPOSE: To compare the electroretinal response associated with the uniform-field electroretinogram (UF-ERG) to that of the pattern electroretinogram (PERG) to checkerboard and bar-grating stimuli. METHODS: UF-ERG and PERG to bars and checkerboard were recorded for 18 visually normal subjects (36 eyes) of mean age 45 years (range 20-75). UF-ERG was recorded to the increment and decrement of a 200-ms duration luminance modulation. Luminance onset and offset UF-ERG responses were averaged to produce a simulation of the PERG response. The mean amplitude and implicit time for the P50 and N95 potentials of actual and simulated PERG responses were recorded for each eye in the cohort. RESULTS: The simulated PERG waveform resulting from arithmetic averaging of the UF-ERG to luminance increment and decrement was characterized by prominent positive and negative components resembling those of the P50 and N95 PERG potentials. Implicit timing of the P50 potential was lengthened in the actual PERG to bars and checks relative to that of the simulation (P < 0.05, P < 0.001). Amplitude of the N95 potential was greater in the PERG to bars than in the PERG to checks (P < 0.05) or the simulated PERG (P < 0.001). The amplitude and implicit timing of all waveform components were significantly correlated between the actual and simulated PERG. CONCLUSIONS: The UF-ERG to light onset and offset can be reliably recorded in human subjects. The extent to which the simulated PERG recapitulates the actual PERG response is better with checkerboard rather than bar-grating stimuli.

The Diagnostic Utility of Multifocal Electroretinography in Detecting Chloroquine and Hydroxychloroquine Retinal Toxicity.

PURPOSE: To evaluate multifocal electroretinography (mfERG) as a screening test for detecting hydroxychloroquine and chloroquine toxicity. DESIGN: Diagnostic accuracy study. METHODS: Patients referred to the University of Ottawa for hydroxychloroquine or chloroquine retinopathy screening during 2011-2014 underwent 10-2 automated visual field, spectral domain optical coherence tomography, and mfERG testing. Patients with amblyopia, high myopia or hyperopia, coexisting retinal disease, or prior surgery were excluded. Abnormalities in parafoveal ring amplitudes or ring ratios were considered a positive mfERG result. We used the definition for hydroxychloroquine and chloroquine toxicity provided by the 2016 American Academy of Ophthalmology recommendations. Area under the curve (AUC) for each mfERG parameter and the sensitivity and specificity of mfERG were calculated. Logistic regression was used to model the effect of covariates in receiver operating characteristic (ROC) analyses. RESULTS: In total, 63 patients (47 female, 16 male) were included. Of 120 eyes, 16 (13.3%) had toxicity according to the American Academy of Ophthalmology guidelines, and 39 (32.5%) had positive mfERG findings. mfERG was found to have a sensitivity of 1.00 (95% CI 0.79-1.00) and a specificity of 0.78 (95% CI 0.69-0.85). Ring 2 amplitude had the best performance among all parameters (AUC 0.97, 95% CI 0.94-1.00). Ring 2 amplitude decreased linearly with increasing cumulative dose and daily dose. CONCLUSIONS: The high sensitivity of parafoveal depression on mfERG and its relationship to cumulative and daily dose illustrates an important role for objective functional testing. The high false-positive rate suggests a potential period where physiologic dysfunction is detected objectively on mfERG before structural change on spectral domain optical coherence tomography.

Overexpression of the X-Linked Inhibitor of Apoptosis Protects Against Retinal Degeneration in a Feline Model of Retinal Detachment.

Retinal detachment is an acute disorder in humans that is caused by trauma or disease, and it can often lead to permanent visual deficits that result from the death of photoreceptors in the retina. The final pathway for photoreceptor cell death is apoptosis and necroptosis. The X-linked inhibitor of apoptosis (XIAP) has been shown to block both of these cell death pathways. This study tested the effects of XIAP on photoreceptor survival in a feline model of retinal detachment. The study was performed in 12 cats, divided into two experimental groups. Six animals received a subretinal injection of adeno-associated virus (AAV) carrying XIAP, and six animals received AAV carrying green fluorescent protein (GFP) as a control. Three weeks after viral delivery, retinas were detached by injecting C3F8 gas into the subretinal space. Optical coherence tomography revealed that the retinal detachments resolved within 3-6 weeks as the gas was slowly resorbed. Analysis of histological sections through the plane of the detachment showed significant preservation of the photoreceptor layer in AAV-XIAP-treated animals compared to AAV-GFP-treated animals at 9 weeks after the detachment. XIAP-treated detached retinas were similar to intact controls. These studies support the potential for XIAP therapy in the treatment of human retinal detachment.

Retinal interneuron survival requires non-cell-autonomous Atrx activity.

ATRX is a chromatin remodeling protein that is mutated in several intellectual disability disorders including alpha-thalassemia/mental retardation, X-linked (ATR-X) syndrome. We previously reported the prevalence of ophthalmological defects in ATR-X syndrome patients, and accordingly we find morphological and functional visual abnormalities in a mouse model harboring a mutation occurring in ATR-X patients. The visual system abnormalities observed in these mice parallels the Atrx-null retinal phenotype characterized by interneuron defects and selective loss of amacrine and horizontal cells. The mechanisms that underlie selective neuronal vulnerability and neurodegeneration in the central nervous system upon Atrx mutation or deletion are unknown. To interrogate the cellular specificity of Atrx for its retinal neuroprotective functions, we employed a combination of temporal and lineage-restricted conditional ablation strategies to generate five different conditional knockout mouse models, and subsequently identified a non-cell-autonomous requirement for Atrx in bipolar cells for inhibitory interneuron survival in the retina. Atrx-deficient retinal bipolar cells exhibit functional, structural and molecular alterations consistent with impairments in neuronal activity and connectivity. Gene expression changes in the Atrx-null retina indicate defective synaptic structure and neuronal circuitry, suggest excitotoxic mechanisms of neurodegeneration, and demonstrate that common targets of ATRX in the forebrain and retina may contribute to similar neuropathological processes underlying cognitive impairment and visual dysfunction in ATR-X syndrome.

The Development of a Cat Model of Retinal Detachment and Re-attachment.

We present an optimized surgical technique for feline retinal detachment which allows for natural re-attachment, reduces retinal scarring and vitreal bands, and allows central placement of the detachment in close proximity to the optic nerve. This enables imaging via Optical Coherence Tomography (OCT) and multifocal electroretinography (mfERG) analysis. Ideal detachment conditions involve a lensectomy followed by a three-port pars plana vitrectomy. A 16-20 % retinal detachment is induced by injecting 8 % C3F8 gas into the subretinal space in the central retina with a 42G cannula. The retinal detachment resolves approximately 6 weeks post-surgery. Imaging is enhanced by using a 7.5 and 20 diopter lens for OCT and mfERG fundus imaging, respectively, to compensate for the removed lens.

Whole-Retina Reduced Electrophysiological Activity in Mice Bearing Retina-Specific Deletion of Vesicular Acetylcholine Transporter.

BACKGROUND: Despite rigorous characterization of the role of acetylcholine in retinal development, long-term effects of its absence as a neurotransmitter are unknown. One of the unanswered questions is how acetylcholine contributes to the functional capacity of mature retinal circuits. The current study investigates the effects of disrupting cholinergic signalling in mice, through deletion of vesicular acetylcholine transporter (VAChT) in the developing retina, pigmented epithelium, optic nerve and optic stalk, on electrophysiology and structure of the mature retina. METHODS & RESULTS: A combination of electroretinography, optical coherence tomography imaging and histological evaluation assessed retinal integrity in mice bearing retina- targeted (embryonic day 12.5) deletion of VAChT (VAChTSix3-Cre-flox/flox) and littermate controls at 5 and 12 months of age. VAChTSix3-Cre-flox/flox mice did not show any gross changes in nuclear layer cellularity or synaptic layer thickness. However, VAChTSix3-Cre-flox/flox mice showed reduced electrophysiological response of the retina to light stimulus under scotopic conditions at 5 and 12 months of age, including reduced a-wave, b-wave, and oscillatory potential (OP) amplitudes and decreased OP peak power and total energy. Reduced a-wave amplitude was proportional to the reduction in b-wave amplitude and not associated with altered a-wave 10%-90% rise time or inner and outer segment thicknesses. SIGNIFICANCE: This study used a novel genetic model in the first examination of function and structure of the mature mouse retina with disruption of cholinergic signalling. Reduced amplitude across the electroretinogram wave form does not suggest dysfunction in specific retinal cell types and could reflect underlying changes in the retinal and/or extraretinal microenvironment. Our findings suggest that release of acetylcholine by VAChT is essential for the normal electrophysiological response of the mature mouse retina.

Is Acute Zonal Occult Outer Retinopathy an Autoimmune Condition? A Case Report and Literature Review.

A 42-year-old woman with multiple sclerosis presented with focal decreased vision and photopsia in the left eye. Funduscopy and fluorescein angiography revealed focal chorioretinal atrophy, vascular attenuation, and bone spicules. Electroretinography revealed interocular reduction in b-wave amplitude, and Goldmann visual field perimetry studies revealed an inferior scotoma. The authors performed a literature review and conclude that the prevalence of acute zonal occult outer retinopathy in patients with autoimmune conditions may suggest that the condition is autoimmune in nature. Clinical history as well as funduscopic and retinal investigations are important in diagnosing acute zonal occult outer retinopathy.

Hydroxychloroquine and chloroquine retinopathy: a systematic review evaluating the multifocal electroretinogram as a screening test.

PURPOSE: To determine the validity of multifocal electroretinography (mfERG) as a screening tool for detecting chloroquine (Aralen, Sanofi Aventis, Bridgewater, NJ) (CQ) and hydroxychloroquine (Plaquenil, Covis Pharmaceuticals, Inc, Zug, Switzerland) (HCQ) retinal toxicity in patients using these medications. To evaluate the sensitivity and specificity of mfERG when compared with automated visual fields (AVFs), fundus autofluorescence (FAF), and optical coherence tomography (OCT). CLINICAL RELEVANCE: The 2011 American Academy of Ophthalmology recommendations on screening for CQ/HCQ retinopathy recommended a shift toward more objective testing modalities. Multifocal electroretinography may be effective in detecting functional change before irreversible structural damage from CQ/HCQ toxicity. METHODS: We performed a search for records reporting the use of mfERG for screening CQ/HCQ retinopathy in MEDLINE (PubMed and OVID), EMBASE, and Web of Science, and assessed these using the QUADAS-2 risk of bias tool. We conducted an analysis of 23 individual studies and their reported individual patient data (449 eyes of 243 patients) published from January 2000 to December 2014. RESULTS: Multifocal electroretinography had the greatest proportion of positive test results, followed by AVF. The pooled sensitivity and specificity of mfERG were 90% (95% confidence interval [CI], 0.62-0.98) and 52% (CI, 0.29-0.74), respectively, with AVF as reference standard (13 studies). Sensitivity was high, but specificity was variable when OCT, FAF, and the positivity of 2 of 3 tests was used as the reference standard. When verified against AVF as the reference test, patients with a false-positive mfERG result received higher HCQ cumulative doses (1068 g) than patients with true-negative (658 g, P < 0.01) and false-negative (482 g, P < 0.01) results. CONCLUSIONS: Multifocal electroretinography was shown to have a high sensitivity but variable specificity when verified against AVF, OCT, FAF, and a combination of tests. The greater average cumulative dose in the false-positive group compared with the true-negative group when mfERG was verified against AVF suggests that mfERG may have the ability to detect cases of toxicity earlier than other modalities. There is an unclear risk of bias in the available evidence, and future studies should adhere to Standards for Reporting of Diagnostic Accuracy reporting guidelines.

Remission of nonparaneoplastic autoimmune retinopathy after minimal steroid treatment.

PURPOSE: To describe the clinical findings in a patient demonstrating recovery from nonparaneoplastic autoimmune retinopathy after a minimal course of steroid treatment. METHODS: Clinical presentation was documented, and paraclinical tests were obtained using Humphrey automated perimetry for visual fields, Western blotting for antiretinal antibodies, and electroretinography for evaluation of rod and cone function. RESULTS: Initial presentation revealed marked visual field deficits, electroretinographic dysfunction, and the presence of α-enolase autoantibodies. After a brief course of oral corticosteroids, the patient demonstrated improvement in visual fields, disappearance of α-enolase autoantibodies, partial recovery of the cone on-response, and complete recovery of the rod response. CONCLUSION: This case is distinguished from previous reports by the rapidity and degree of recovery, the brevity of treatment required, and the unique electroretinographic recovery pattern with concomitant disappearance of α-enolase autoantibodies. These findings suggest a pathologic role for α-enolase autoantibodies in autoimmune rod bipolar cell dysfunction. Identification of other cases exhibiting such improvements and associated autoantibody activity may expand our understanding of nonparaneoplastic autoimmune retinopathy disease pathogenesis.

Efficacy of SLO-Microperimetry and Humphrey for evaluating macular sensitivity changes in advanced glaucoma.

OBJECTIVE: To compare the efficacy of scanning laser ophthalmoscope microperimetry (SLO-MP) and Humphrey visual fields in detecting macular sensitivity changes in advanced glaucoma. DESIGN: Prospective cohort study. PARTICIPANTS: 25 patients with advanced primary open angle glaucoma and 2 consecutive abnormal Humphrey 10-2 SITA Standard visual field tests. METHODS: Thirty-six eyes of 25 patients with 2 consecutive abnormal Humphrey 10-2 SITA Standard (H10) visual fields were retested with a modified 10-2 SLO-MP within 3 months of the last reliable H10. A standardized grid was used to mark the macula. Primary outcome was change in mean macular sensitivity (dB; H10 and SLO-MP) in relation to mean macular retinal nerve fibre layer (RNFL) thickness (µm) by SLO- optical coherence tomography (SLO-OCT). Secondary outcome was comparison of reliability indices for both tests. Linear regression was used for analysis. RESULTS: Mean macular sensitivity was significantly lower in SLO-MP (9.33 ± 3.37 dB) than H10 (18.83 ± 6.46 dB; p < 0.0001). Mean macular RNFL thickness correlated significantly with retinal sensitivity by both SLO-MP (r = 0.39, p < 0.02) and H10 (r = 0.37, p < 0.03). Fixation losses were better controlled in SLO-MP (0.38 ± 1.1) than H10 (4.28 ± 7.9; p = 0.008). False-positive responses were similar (SLO-MP: 2.25 ± 4.53, H10: 1.78 ± 3.33; p = 0.80). A statistically significant difference was noted in the false-negative responses (SLO-MP: 26.87 ± 25.24, H10: 5.33 ± 9.70; p < 0.0001). CONCLUSIONS: Macular sensitivity determined by both H10 and SLO-MP correlates significantly with mean macular RNFL thickness measured by SLO-OCT. Precise localization of the macula in SLO-MP results in lower fixation losses. Detection of denser field defects by SLO-MP results in higher false-negative responses. A larger sample size is needed to further study the value of this diagnostic tool.

Recovery of function following regeneration of the damaged retina in the adult newt, Notophthalmus viridescens.

The red-spotted newt, Notophthalmus viridescens, is one of few adult vertebrate organisms that has retained the remarkable ability to regenerate a complete retina following injury or removal. The aim of this study was to develop a non-invasive method to monitor recovery of components within the retinal circuitry, in vivo, following surgical removal (retinectomy) of the adult newt retina. A novel and reproducible protocol was established for full-field electroretinography in the intact newt retina. Electroretinograms (ERGs) were measured at the corneal surface. The effects of dilation and external body temperature on the ERG amplitudes were measured as well as the reproducibility in recording ERGs in the same animal over time. Retinectomies were conducted on 15 newts, and the a- and b-wave amplitudes were measured prior to retinectomy and at various timepoints after retinectomy. Surgical removal of the retina resulted in an initial loss of ERG a- and b-waves, representing loss of photoreceptor cells and cells of the inner nuclear layer. The ERG amplitudes recovered to baseline levels by 15 weeks post-retinectomy, indicative of subsequent restoration of retinal function after regeneration.

The novel use of bevacizumab and photodynamic therapy in the treatment of best disease.

PURPOSE: To report on the novel use of bevacizumab (Avastin) in combination with photodynamic therapy (PDT) for the treatment of Best disease with choroidal neovascularization. METHODS: A 17-year-old girl with Best disease, choroidal neovascularization, and subretinal hemorrhage in the right eye was treated with bevacizumab and PDT. RESULTS: The use of bevacizumab and PDT was associated with a change in vision from counting fingers to 20/25 and was well tolerated by the patient. CONCLUSION: The use of bevacizumab and PDT in the management of Best disease seems to be a very effective method of treatment showing improvement in visual acuity.This is the first case to be reported in the literature of bevacizumab in combination with PDT for the treatment of choroidal neovascularization in Best disease.

Retinal effects of 6 months of daily use of tadalafil or sildenafil.

OBJECTIVE: To assess changes in electroretinography (ERG) and other retinal function parameters during 6 months of daily use of tadalafil, sildenafil citrate, or placebo. METHODS: Subjects were randomized to use of a placebo (n=82), 5 mg of tadalafil (n=85), or 50 mg of sildenafil (n=77) daily for 6 months. Electroretinographs were recorded using the International Society for Clinical Electrophysiology of Vision (ISCEV) protocol and standardized ERG equipment at all 15 study sites. Other tests of ocular anatomy and visual function were performed at each assessment. MAIN OUTCOME MEASURES: The primary outcome was the average mean change for both eyes from baseline to endpoint in ERG b-wave amplitude using dark-adapted combined standard response to a bright ISCEV standard flash. Secondary endpoints were other ERG parameter changes, visual acuity, number of errors in color discrimination testing, mean deviation in automated visual field testing, and intraocular pressure (IOP). RESULTS: No significant differences were found between treatment/placebo groups for the primary outcome, most other ERG variables, visual function, IOP, or anatomic assessments. The medications were well tolerated. CONCLUSIONS: No abnormalities in ERG or visual function and no treatment-related findings suggestive of drug toxicity are associated with daily administration of tadalafil or sildenafil for 6 months. APPLICATION TO CLINICAL PRACTICE: Assessed visual safety of tadalafil/sildenafil administered daily over a prolonged period. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00333281.

Optimal optical coherence tomography-based measures in the diagnosis of clinically significant macular edema: retinal volume vs foveal thickness.

OBJECTIVE: To compare optical coherence tomography-based measures of retinal thickness and volume as quantitative tests for clinically significant macular edema (CSME). DESIGN: Diagnostic validation study. METHODS: Sixty-five eyes with diabetic retinopathy underwent stereo photographic and optical coherence tomographic examination. Stereo photographs were examined in a masked fashion to determine the presence or absence of CSME according to criteria from the Early Treatment Diabetic Retinopathy Study. Optical coherence tomography-based measurements of central foveal thickness as well as retinal volumes within a series of radii of fixation were generated. The main outcome measures were areas under receiver operating characteristic curves. Likelihood ratios, sensitivities, and specificities for the diagnosis of CSME were also evaluated. RESULTS: Retinal volumes within radii of 0.50 mm and 1.11 mm of fixation and central foveal thickness were the best variables for discriminating between those with and without CSME as evidenced by analysis of receiver operating characteristic curves. There were no significant differences among these 3 variables in their performance as diagnostic tests for CSME. CONCLUSIONS: Optical coherence tomography-based retinal volume and central foveal thickness variables display comparable abilities to discriminate between those with and without CSME. Both measures may have clinical applications as quantitative diagnostic tests for CSME.

Effect of eccentric and inconsistent fixation on retinal optical coherence tomography measures.

OBJECTIVE: To assess the relative stabilities of optical coherence tomography (OCT)-based retinal volume and central foveal thickness measurements in the setting of eccentric or inconsistent fixation. METHODS: Ten healthy right eyes underwent multiple macular OCT centered at fixation. To model the effect of eccentric or inconsistent fixation, OCT was repeated with scan centers precisely shifted by 0.50, 1.00, and 1.50 mm in each of 4 directions. At each scan location, retinal volumes within a series of radii of the scan center, as well as central foveal thickness, were calculated. The main outcome measure was the percentage effect of decentered scanning on each OCT-based variable. RESULTS: Central foveal thickness was the variable most affected in this model of eccentric and inconsistent fixation. This variable demonstrated changes from baseline-centered scans of up to 69.4%. Retinal volumes within a radii of the scan center measuring 1.11 mm or greater were least affected by decentered scanning, demonstrating maximum changes from baseline-centered scans of only 15.7% (P<.001 vs foveal thickness). CONCLUSION: Optical coherence tomography-based retinal volume quantification provides a more stable measure than foveal thickness in the setting of eccentric or inconsistent fixation as may occur in the setting of macular pathologic conditions.